1887

Abstract

Immunomodulators have been shown to improve the outcome of severe pneumonia. We have previously shown that mycophenolic acid (MPA), an immunomodulator, has antiviral activity against influenza A/WSN/1933(H1N1) using a high-throughput chemical screening assay. This study further investigated the antiviral activity and mechanism of action of MPA against contemporary clinical isolates of influenza A and B viruses. The 50 % cellular cytotoxicity (CC) of MPA in Madin Darby canine kidney cell line was over 50 µM. MPA prevented influenza virus-induced cell death in the cell-protection assay, with significantly lower IC for influenza B virus B/411 than that of influenza A(H1N1)pdm09 virus H1/415 (0.208 vs 1.510 µM, =0.0001). For H1/415, MPA interfered with the early stage of viral replication before protein synthesis. For B/411, MPA may also act at a later stage since MPA was active against B/411 even when added 12 h post-infection. Virus-yield reduction assay showed that the replication of B/411 was completely inhibited by MPA at concentrations ≥0.78 µM, while there was a dose-dependent reduction of viral titer for H1/415. The antiviral effect of MPA was completely reverted by guanosine supplementation. Plaque reduction assay showed that MPA had antiviral activity against eight different clinical isolates of A(H1N1), A(H3N2), A(H7N9) and influenza B viruses (IC <1 µM). In summary, MPA has broad-spectrum antiviral activity against human and avian-origin influenza viruses, in addition to its immunomodulatory activity. Together with a high chemotherapeutic index, the use of MPA as an antiviral agent should be further investigated .

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000512
2016-08-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/8/1807.html?itemId=/content/journal/jgv/10.1099/jgv.0.000512&mimeType=html&fmt=ahah

References

  1. Allison A. C., Eugui E. M. 2000; Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47:85–118 [View Article][PubMed]
    [Google Scholar]
  2. Anonymous. Mycophenolic acid. In DRUGDEX® System [Internet database], Micromedex® 2.0. Accessed on 23 July 2013
    [Google Scholar]
  3. Baker S. F., Nogales A., Finch C., Tuffy K. M., Domm W., Perez D. R., Topham D. J., Martínez-Sobrido L. 2014; Influenza A and B virus intertypic reassortment through compatible viral packaging signals. J Virol 88:10778–10791 [View Article][PubMed]
    [Google Scholar]
  4. Baranovich T., Wong S. S., Armstrong J., Marjuki H., Webby R. J., Webster R. G., Govorkova E. A. 2013; T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol 87:3741–3751 [View Article][PubMed]
    [Google Scholar]
  5. Beduschi M. G., Guimarães C. L., Buss Z. S., Dalmarco E. M. 2013; Mycophenolate mofetil has potent anti-inflammatory actions in a mouse model of acute lung injury. Inflammation 36:729–737 [View Article][PubMed]
    [Google Scholar]
  6. Belardo G., Cenciarelli O., La Frazia S., Rossignol J. F., Santoro M. G. 2015; Synergistic effect of nitazoxanide with neuraminidase inhibitors against influenza A viruses in vitro . Antimicrob Agents Chemother 59:1061–1069 [View Article]
    [Google Scholar]
  7. Blaising J., Polyak S. J., Pécheur E. I. 2014; Arbidol as a broad-spectrum antiviral: an update. Antiviral Res 107:84–94 [View Article][PubMed]
    [Google Scholar]
  8. Blum C. A., Nigro N., Briel M., Schuetz P., Ullmer E., Suter-Widmer I., Winzeler B., Bingisser R., Elsaesser H. et al. 2015; Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 385:1511–1518 [View Article][PubMed]
    [Google Scholar]
  9. Burnham A. J., Baranovich T., Govorkova E. A. 2013; Neuraminidase inhibitors for influenza B virus infection: efficacy and resistance. Antiviral Res 100:520–534 [View Article][PubMed]
    [Google Scholar]
  10. Cao R. Y., Xiao J. H., Cao B., Li S., Kumaki Y., Zhong W. 2014; Inhibition of novel reassortant avian influenza H7N9 virus infection in vitro with three antiviral drugs, oseltamivir, peramivir and favipiravir. Antivir Chem Chemother 23:237–240 [View Article][PubMed]
    [Google Scholar]
  11. Carr S., Ilyushina N. A., Franks J., Adderson E. E., Caniza M., Govorkova E. A., Webster R. G. 2011; Oseltamivir-resistant influenza A and B viruses pre- and postantiviral therapy in children and young adults with cancer. Pediatr Infect Dis J 30:284–288 [View Article][PubMed]
    [Google Scholar]
  12. Chan J. F., Chan K. H., Kao R. Y., To K. K., Zheng B. J., Li C. P., Li P. T., Dai J., Mok F. K. et al. 2013a; Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 67:606–616 [CrossRef]
    [Google Scholar]
  13. Chan K. H., To K. K., Chan J. F., Li C. P., Chen H., Yuen K. Y. 2013b; Analytical sensitivity of seven point-of-care influenza virus detection tests and two molecular tests for detection of avian origin H7N9 and swine origin H3N2 variant influenza A viruses. J Clin Microbiol 51:3160–3161 [CrossRef]
    [Google Scholar]
  14. Chan K. H., To K. K., Hung I. F., Zhang A. J., Chan J. F., Cheng V. C., Tse H., Che X. Y., Chen H. et al. 2011; Differences in antibody responses of individuals with natural infection and those vaccinated against pandemic H1N1 2009 influenza. Clin Vaccine Immunol 18:867–873 [View Article][PubMed]
    [Google Scholar]
  15. Chapuis A. G., Paolo Rizzardi G., D'Agostino C., Attinger A., Knabenhans C., Fleury S., Acha-Orbea H., Pantaleo G. 2000; Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo . Nat Med 6:762–768 [View Article][PubMed]
    [Google Scholar]
  16. Chen Y., Liang W., Yang S., Wu N., Gao H., Sheng J., Yao H., Wo J., Fang Q. et al. 2013; Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 381:1916–1925 [View Article][PubMed]
    [Google Scholar]
  17. Cheng V. C., To K. K., Tse H., Hung I. F., Yuen K. Y. 2012; Two years after pandemic influenza A/2009/H1N1: what have we learned?. Clin Microbiol Rev 25:223–263 [View Article][PubMed]
    [Google Scholar]
  18. Cline J. C., Nelson J. D., Gerzon K., Williams R. H., Delong D. C. 1969; In vitro antiviral activity of mycophenolic acid and its reversal by guanine-type compounds. Appl Microbiol 18:14–20[PubMed]
    [Google Scholar]
  19. ClinicalTrials.gov Phase 3 Efficacy and Safety Study of Favipiravir for Treatment of Uncomplicated Influenza in Adults. Available at http://www.clinicaltrials.gov/show/NCT02008344 Accessed on 22 August 2014
  20. Daikoku T., Yoshida Y., Okuda T., Shiraki K. 2014; Characterization of susceptibility variants of influenza virus grown in the presence of T-705. J Pharmacol Sci 126:281–284[PubMed] [CrossRef]
    [Google Scholar]
  21. Diamond M. S., Zachariah M., Harris E. 2002; Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology 304:211–221 [View Article][PubMed]
    [Google Scholar]
  22. Dobson J., Whitley R. J., Pocock S., Monto A. S. 2015; Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 385:1729–1737 [View Article][PubMed]
    [Google Scholar]
  23. Escuret V., Collins P. J., Casalegno J. S., Vachieri S. G., Cattle N., Ferraris O., Sabatier M., Frobert E., Caro V. et al. 2014; A novel I221L substitution in neuraminidase confers high-level resistance to oseltamivir in influenza B viruses. J Infect Dis 210:1260–1269 [View Article][PubMed]
    [Google Scholar]
  24. Fischer A., Brown K. K., Du Bois R. M., Frankel S. K., Cosgrove G. P., Fernandez-Perez E. R., Huie T. J., Krishnamoorthy M., Meehan R. T. et al. 2013; Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol 40:640–646 [View Article][PubMed]
    [Google Scholar]
  25. Furuta Y., Gowen B. B., Takahashi K., Shiraki K., Smee D. F., Barnard D. L. 2013; Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 100:446–454 [View Article][PubMed]
    [Google Scholar]
  26. Furuta Y., Takahashi K., Kuno-Maekawa M., Sangawa H., Uehara S., Kozaki K., Nomura N., Egawa H., Shiraki K. 2005; Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother 49:981–986 [View Article]
    [Google Scholar]
  27. Garg S., Moore Z., Lee N., McKenna J., Bishop A., Fleischauer A., Springs C. B., Nguyen H. T., Sheu T. G. et al. 2013; A cluster of patients infected with I221V influenza B virus variants with reduced oseltamivir susceptibility—North Carolina and South Carolina, 2010-2011. J Infect Dis 207:966–973 [View Article][PubMed]
    [Google Scholar]
  28. Haffizulla J., Hartman A., Hoppers M., Resnick H., Samudrala S., Ginocchio C., Bardin M., Rossignol J. F. US Nitazoxanide Influenza Clinical Study Group 2014; Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis 14:609–618 [View Article][PubMed]
    [Google Scholar]
  29. Heneghan C. J., Onakpoya I., Thompson M., Spencer E. A., Jones M., Jefferson T. 2014; Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 348:g2547 [View Article][PubMed]
    [Google Scholar]
  30. Hung I. F., To K. K., Lee C. K., Lee K. L., Chan K., Yan W. W., Liu R., Watt C. L., Chan W. M. et al. 2011; Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 52:447–456 [View Article][PubMed]
    [Google Scholar]
  31. Hung I. F., To K. K., Lee C. K., Lee K. L., Yan W. W., Chan K., Chan W. M., Ngai C. W., Law K. I. et al. 2013; Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest 144:464–473 [View Article][PubMed]
    [Google Scholar]
  32. Jefferson T., Jones M., Doshi P., Spencer E. A., Onakpoya I., Heneghan C. J. 2014; Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 348:g2545 [View Article][PubMed]
    [Google Scholar]
  33. Kao R. Y., Yang D., Lau L. S., Tsui W. H., Hu L., Dai J., Chan M. P., Chan C. M., Wang P. et al. 2010; Identification of influenza A nucleoprotein as an antiviral target. Nat Biotechnol 28:600–605 [View Article][PubMed]
    [Google Scholar]
  34. Khan M., Dhanwani R., Patro I. K., Rao P. V., Parida M. M. 2011; Cellular IMPDH enzyme activity is a potential target for the inhibition of Chikungunya virus replication and virus induced apoptosis in cultured mammalian cells. Antiviral Res 89:1–8 [View Article][PubMed]
    [Google Scholar]
  35. Kiselev O. I., Maleev V. V., Deeva ÉG., Leneva I. A., Sel'kova E. P., Osipova E. A., Obukhov A. A., Nadorov S. A., Kulikova E. V. 2015; [Clinical efficacy of arbidol (umifenovir) in the therapy of influenza in adults: preliminary results of the multicenter double-blind randomized placebo-controlled study ARBITR]. Ter Arkh 87:88–96 (in Russian) [View Article][PubMed]
    [Google Scholar]
  36. Lejal N., Tarus B., Bouguyon E., Chenavas S., Bertho N., Delmas B., Ruigrok R. W., Di Primo C., Slama-Schwok A. 2013; Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. Antimicrob Agents Chemother 57:2231–2242 [View Article]
    [Google Scholar]
  37. Li I. W., Chan K. H., To K. W., Wong S. S., Ho P. L., Lau S. K., Woo P. C., Tsoi H. W., Chan J. F. et al. 2009; Differential susceptibility of different cell lines to swine-origin influenza A H1N1, seasonal human influenza A H1N1, and avian influenza A H5N1 viruses. J Clin Virol 46:325–330 [View Article][PubMed]
    [Google Scholar]
  38. Luke T. C., Kilbane E. M., Jackson J. L., Hoffman S. L. 2006; Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?. Ann Intern Med 145:599–609[PubMed] [CrossRef]
    [Google Scholar]
  39. Mok B. W., Song W., Wang P., Tai H., Chen Y., Zheng M., Wen X., Lau S. Y., Wu W. L. et al. 2012; The NS1 protein of influenza A virus interacts with cellular processing bodies and stress granules through RNA-associated protein 55 (RAP55) during virus infection. J Virol 86:12695–12707 [View Article][PubMed]
    [Google Scholar]
  40. Morgenstern B., Michaelis M., Baer P. C., Doerr H. W., Cinatl J. 2005; Ribavirin and interferon-beta synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. Biochem Biophys Res Commun 326:905–908 [View Article][PubMed]
    [Google Scholar]
  41. Muthuri S. G., Venkatesan S., Myles P. R., Leonardi-Bee J., Al Khuwaitir T. S., Al Mamun A., Anovadiya A. P., Azziz-Baumgartner E., Báez C. et al. 2014; Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2:395–404 [View Article][PubMed]
    [Google Scholar]
  42. Ölschläger S., Neyts J., Günther S. 2011; Depletion of GTP pool is not the predominant mechanism by which ribavirin exerts its antiviral effect on Lassa virus. Antiviral Res 91:89–93 [View Article][PubMed]
    [Google Scholar]
  43. Pan M., Gao R., Lv Q., Huang S., Zhou Z., Yang L., Li X., Zhao X., Zou X. et al. 2016; Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings. J Infect 72:52–59 [View Article][PubMed]
    [Google Scholar]
  44. Priore S. F., Moss W. N., Turner D. H. 2012; Influenza A virus coding regions exhibit host-specific global ordered RNA structure. PLoS One 7:e35989 [View Article][PubMed]
    [Google Scholar]
  45. Priore S. F., Moss W. N., Turner D. H. 2013; Influenza B virus has global ordered RNA structure in (+) and (-) strands but relatively less stable predicted RNA folding free energy than allowed by the encoded protein sequence. BMC Res Notes 6:330 [View Article][PubMed]
    [Google Scholar]
  46. Qiu L. W., Liao Z. Y., Wang Y. D., Ding X. X., Di B., Yuen K. Y., Che X. Y. 2009; Development and application of monoclonal antibodies-based antigen capture ELISA for detecting nucleocapsid protein of Influenza B virus. Guangdong Medecal Journal 30:1435–1438
    [Google Scholar]
  47. Sebastian L., Madhusudana S. N., Ravi V., Desai A. 2011; Mycophenolic acid inhibits replication of Japanese encephalitis virus. Chemotherapy 57:56–61 [View Article][PubMed]
    [Google Scholar]
  48. Sheu T. G., Deyde V. M., Okomo-Adhiambo M., Garten R. J., Xu X., Bright R. A., Butler E. N., Wallis T. R., Klimov A. I. et al. 2008; Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother 52:3284–3292 [View Article]
    [Google Scholar]
  49. Smee D. F., Tarbet E. B., Furuta Y., Morrey J. D., Barnard D. L. 2013; Synergistic combinations of favipiravir and oseltamivir against wild-type pandemic and oseltamivir-resistant influenza A virus infections in mice. Future Virol 8:1085–1094 [View Article][PubMed]
    [Google Scholar]
  50. Su S., Chaves S. S., Perez A., D'Mello T., Kirley P. D., Yousey-Hindes K., Farley M. M., Harris M., Sharangpani R. et al. 2014; Comparing clinical characteristics between hospitalized adults with laboratory-confirmed influenza A and B virus infection. Clin Infect Dis 59:252–255 [View Article][PubMed]
    [Google Scholar]
  51. Takashita E., Meijer A., Lackenby A., Gubareva L., Rebelo-de-Andrade H., Besselaar T., Fry A., Gregory V., Leang S. K. et al. 2015; Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013-2014. Antiviral Res 117:27–38 [View Article][PubMed]
    [Google Scholar]
  52. To K. K., Hung I. F., Li I. W., Lee K. L., Koo C. K., Yan W. W., Liu R., Ho K. Y., Chu K. H. et al. 2010; Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 influenza virus infection. Clin Infect Dis 50:850–859 [View Article][PubMed]
    [Google Scholar]
  53. To K. K., Ng K. H., Que T. L., Chan J. M., Tsang K. Y., Tsang A. K., Chen H., Yuen K. Y. 2012; Avian influenza A H5N1 virus: a continuous threat to humans. Emerg Microbes Infect 1:e25 [View Article][PubMed]
    [Google Scholar]
  54. To K. K., Chan J. F., Chen H., Li L., Yuen K. Y. 2013; The emergence of influenza A H7N9 in human beings 16 years after influenza A H5N1: a tale of two cities. Lancet Infect Dis 13:809–821 [View Article][PubMed]
    [Google Scholar]
  55. To K. K., Chan J. F., Yuen K. Y. 2014a; Viral lung infections: epidemiology, virology, clinical features, and management of avian influenza A(H7N9). Curr Opin Pulm Med 20:225–232 [CrossRef]
    [Google Scholar]
  56. To K. K., Tsang A. K., Chan J. F., Cheng V. C., Chen H., Yuen K. Y. 2014b; Emergence in China of human disease due to avian influenza A(H10N8)-cause for concern?. J Infect 68:205–215 [CrossRef]
    [Google Scholar]
  57. To K. K., Zhang A. J., Chan A. S., Li C., Cai J. P., Lau C. C., Li C. G., Jahan A. S., Wu W. L. et al. 2015; Recombinant influenza A virus hemagglutinin HA2 subunit protects mice against influenza A(H7N9) virus infection. Arch Virol 160:777–786 [View Article][PubMed]
    [Google Scholar]
  58. Torres A., Sibila O., Ferrer M., Polverino E., Menendez R., Mensa J., Gabarrús A., Sellarés J., Restrepo M. I. et al. 2015; Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 313:677–686 [View Article][PubMed]
    [Google Scholar]
  59. Van Gelder T., Hesselink D. A. 2015; Mycophenolate revisited. Transpl Int 28:508–515 [View Article][PubMed]
    [Google Scholar]
  60. Vethe N. T., Bremer S., Rootwelt H., Bergan S. 2008; Pharmacodynamics of mycophenolic acid in CD4+ cells: a single-dose study of IMPDH and purine nucleotide responses in healthy individuals. Ther Drug Monit 30:647–655 [View Article][PubMed]
    [Google Scholar]
  61. Villarroel M. C., Hidalgo M., Jimeno A. 2009; Mycophenolate mofetil: An update. Drugs of Today 45:521–532 [View Article][PubMed]
    [Google Scholar]
  62. Wakai C., Iwama M., Mizumoto K., Nagata K. 2011; Recognition of cap structure by influenza B virus RNA polymerase is less dependent on the methyl residue than recognition by influenza A virus polymerase. J Virol 85:7504–7512 [View Article][PubMed]
    [Google Scholar]
  63. Wang C. H., Chung F. T., Lin S. M., Huang S. Y., Chou C. L., Lee K. Y., Lin T. Y., Kuo H. P. 2014a; Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit Care Med 42:313–321 [CrossRef]
    [Google Scholar]
  64. Wang Y., Zhou X., Debing Y., Chen K., Van Der Laan L. J., Neyts J., Janssen H. L., Metselaar H. J., Peppelenbosch M. P. et al. 2014b; Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology 146:1775–1783 [View Article][PubMed]
    [Google Scholar]
  65. Watanabe T., Kawakami E., Shoemaker J. E., Lopes T. J., Matsuoka Y., Tomita Y., Kozuka-Hata H., Gorai T., Kuwahara T. et al. 2014; Influenza virus-host interactome screen as a platform for antiviral drug development. Cell Host Microbe 16:795–805 [View Article][PubMed]
    [Google Scholar]
  66. Watanabe T., Kawaoka Y. 2015; Influenza virus-host interactomes as a basis for antiviral drug development. Curr Opin Virol 14:71–78 [View Article][PubMed]
    [Google Scholar]
  67. Wunderlich K., Juozapaitis M., Mänz B., Mayer D., Götz V., Zöhner A., Wolff T., Schwemmle M., Martin A. 2010; Limited compatibility of polymerase subunit interactions in influenza A and B viruses. J Biol Chem 285:16704–16712 [View Article][PubMed]
    [Google Scholar]
  68. Yang Y. F., Tan D. M., Xie Y. T., Zhao W., Hou Z. H., Zhong Y. D. 2008; Mycophenolate mofetil prevents lethal acute liver failure in mice induced by bacille Calmette-Guérin and lipopolysaccharide. J Gastroenterol Hepatol 23:611–618 [View Article][PubMed]
    [Google Scholar]
  69. Ye L., Li J., Zhang T., Wang X., Wang Y., Zhou Y., Liu J., Parekh H. K., Ho W. 2012; Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells. Virus Res 168:33–40 [View Article][PubMed]
    [Google Scholar]
  70. Yu L., Wang Z., Chen Y., Ding W., Jia H., Chan J. F., To K. K., Chen H., Yang Y. et al. 2013; Clinical, virological, and histopathological manifestations of fatal human infections by avian influenza A(H7N9) virus. Clin Infect Dis 57:1449–1457 [View Article][PubMed]
    [Google Scholar]
  71. Yuen K. Y., Chan P. K., Peiris M., Tsang D. N., Que T. L., Shortridge K. F., Cheung P. T., To W. K., Ho E. T. et al. 1998; Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 351:467–471[PubMed] [CrossRef]
    [Google Scholar]
  72. Zheng B. J., Chan K. W., Lin Y. P., Zhao G. Y., Chan C., Zhang H. J., Chen H. L., Wong S. S., Lau S. K. et al. 2008; Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci U S A 105:8091–8096 [View Article][PubMed]
    [Google Scholar]
  73. Zumla A., Memish Z. A., Maeurer M., Bates M., Mwaba P., Al-Tawfiq J. A., Denning D. W., Hayden F. G., Hui D. S. 2014; Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options. Lancet Infect Dis 14:1136–1149 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000512
Loading
/content/journal/jgv/10.1099/jgv.0.000512
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error